Resistin induces chemokine and matrix metalloproteinase production via CAP1 receptor and activation of p38-MAPK and NF-κB signalling pathways in human chondrocytes.

OBJECTIVES: Adipokine resistin is highly expressed in the serum and synovial uid (SF) of patients with knee osteoarthritis (KOA) but its pathogenic role in KOA remains unclear. We aimed to explore the mechanism of resistin/CAP1 in human KOA chondrocytes. METHODS: We enrolled 103 patients with radiographic KOA and 86 healthy participants as controls. Resistin levels in serum and SF were determined by enzyme-linked immunosorbent assay (ELISA). CAP1 expression was measured in cartilage tissues using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot. Effects of resistin on chondrocytes and CAP1 were evaluated via qRT-PCR and co-immunoprecipitation. The roles of CAP1, p38-MAPK, and NF-κB signalling pathways in KOA development were evaluated using adenovirus-mediated CAP1 short hairpin RNA, qRT-PCR, western blot, and ELISA. RESULTS: Resistin expression in serum and SF was elevated in severe radiographic KOA. CAP1 levels were higher in KOA cartilage and were positively correlated with resistin expression. Resistin promoted CCL3, CCL4, MMP13, and ADAMTS-4 expression through the CAP1 receptor. Resistin also directly bound to CAP1, as confirmed by co-immunoprecipitation. CAP1 knockdown in chondrocytes attenuated resistin-induced expression of CCL3, CCL4, MMP13, and ADAMTS-4 and activated p38-MAPK and NF-κB signalling pathways. CONCLUSIONS: Resistin binds CAP1 and upregulates the expression of proinflammatory cytokines and matrix-degrading enzymes via p38-MAPK and NF-κB signalling in human chondrocytes.

An update on the association between metabolic syndrome and osteoarthritis and on the potential role of leptin in osteoarthritis.

Metabolic syndrome (MetS) has been associated with osteoarthritis (OA). Leptin, which is one of the markers of MetS, has been associated with OA pathophysiology. This study aimed to provide an update on the association between MetS and OA and on the potential role of leptin in OA. In this review, we summarized the current knowledge of the association between MetS and OA and updated the evidence on the potential role of leptin in OA. Clinical studies have investigated the epidemiologic association between MetS or its components and OA. Results suggested strong epidemiologic associations between MetS and OA, especially in the Asian population. Animal studies also indicated that metabolic dysregulation may lead to OA pathogenesis. The systemic role of MetS in OA pathophysiology is associated with obesity-related inflammation, the beneficial role of n-3 polyunsaturated fatty acids and deleterious role of cholesterol, physical inactivity, hypertension-induced subchondral ischemia, dyslipidemia-induced ectopic lipid deposition in chondrocytes, hyperglycemia-induced local effects of oxidative stress and advanced glycation end-products, low-grade systemic inflammation, and obesity-related adipokines by inducing the expression of proinflammtory factors. Leptin levels in serum/plasma and synovial fluid were associated with joint pain, radiographic progression, bone formation biomarkers, cartilage volume, knee OA incidence, and total joint arthroplasty in OA patients. Elevated leptin expression and increased effect of leptin on infrapatellar fat pad, synovium, articular cartilage, and bone were also involved in the pathogenesis of OA. Current knowledge indicates a convincing epidemiologic association between MetS and OA, especially in the Asian population. Animal studies have also shown that metabolic dysregulation may lead to OA pathogenesis. Accumulating evidence suggests that leptin may play a potential role in OA pathogenesis. Therefore, leptin and its receptor may be an emerging target for intervention in metabolic-associated OA.

Differential expression of adipokines in the synovium and infrapatellar fat pad of osteoarthritis patients with and without metabolic syndrome.

Objective: To evaluate the expression levels of adipokines in the synovium and infrapatellar fat pad (IPFP) in osteoarthritis (OA) patients with and without metabolic syndrome (MetS). Methods: 120 female patients with OA were enrolled, and 60 healthy women matched body mass index, age, and sex, served as controls. Adipokines levels were measured using a sandwich enzyme-linked immunosorbent assay of the serum of all participants and synovial fluid (SF) of OA patients. Local expression levels of adipokines in the synovium and IPFP were examined by immunohistochemical analysis. The amount of adipokine proteins was analyzed using Western blot, and adipokine mRNA expressions were determined via quantitative real-time polymerase chain reaction (qRT-PCR). Results: Serum leptin levels were significantly higher in the non-MetS-OA group than those in controls (7.97 vs. 4.24 ng/ml, p< 0.001), and even higher leptin levels were found in the MetS-OA group (19.05 ng/ml; p< 0.001 for both). Serum adiponectin levels were significantly lower in the MetS-OA group than those in controls (8.09 vs. 10.07 µg/ml, respectively; p= 0.001). The synovium and IPFP in the MetS-OA group secreted more leptin and less adiponectin than those in the non-MetS-OA group (Leptin: 5.32 vs. 1.28 in synovium, respectively; p= 0.028; 6.44 vs. 0.88 in IPFP, respectively; p= 0.017. Adiponectin: 1.12 vs. 0.12 in synovium, respectively; p= 0.042; 1.07 vs. 0.09 in IPFP, respectively; p= 0.027). Resistin expression levels in the serum, SF, and articular tissues were similar among the groups. Conclusions: Expressions of adipokines were different in the synovium and IPFP of OA patients with and without MetS.

An Update on the Emerging Role of Resistin on the Pathogenesis of Osteoarthritis.

BACKGROUND: Resistin may be involved in the pathogenesis of osteoarthritis (OA), but a systematic understanding of the role of resistin in OA is lacking. METHODS: We reviewed studies that evaluated the role of resistin in OA. The expression levels of resistin in vitro experiments and OA/rheumatoid arthritis (RA) patients were analyzed. We also studied potential resistin receptors and the signaling pathways that these receptors activate, ultimately leading to cartilage degeneration. RESULTS: Resistin levels in both the serum and synovial fluid were higher in OA and RA patients than in healthy subjects. Overall, resistin levels are much higher in serum than in synovial fluid. In human cartilage, resistin induces the expression of proinflammatory factors such as degradative enzymes, leading to the inhibition of cartilage matrix synthesis, perhaps by binding to Toll-like receptor 4 and the adenylyl cyclase-associated protein 1 receptor, which then activates the p38-mitogen-activated phosphate kinase, protein kinase A-cyclic AMP, nuclear factor-κB, and C/enhancer-binding protein ß signaling pathways. CONCLUSION: Resistin levels are higher in OA patients than in healthy controls; however, the precise role of resistin in the pathogenesis of OA needs to be studied further. Resistin may be a novel therapeutic target in OA in the future.

Differential expression of adipokines in knee osteoarthritis patients with and without metabolic syndrome.

PURPOSE: The purpose of this study was to compare adipokines levels in plasma and synovial fluid (SF) between knee osteoarthritis (OA) patients with and without metabolic syndrome (MetS), and to evaluate the associations between adipokines levels and clinical severity of knee osteoarthritis. METHODS: Eighty female patients with knee osteoarthritis were enrolled in the study. These patients were divided into two groups: patients with and without MetS. Clinical severity was evaluated according to visual analogue scale (VAS) pain scores and Western Ontario McMaster University Osteoarthritis Index (WOMAC) scores. Adipokines and soluble leptin receptor levels in plasma and SF were determined by a sandwich enzyme-linked immunosorbent assay. RESULTS: Forty-three (54%) osteoarthritis patients with MetS and 37 (46%) osteoarthritis patients without MetS were enrolled as MetS-OA group and nMetS-OA group, respectively. VAS pain and WOMAC scores were higher in MetS-OA group compared with those in nMets-OA group (p < 0.01). The leptin and free leptin levels in plasma and SF were significantly higher in MetS-OA group than those in nMetS-OA group, while the adiponectin levels were lower (All p < 0.01). Significant differences existed even after adjustment for body mass index (BMI) (p < 0.05). There were no significant associations between adipokines levels and the clinical severity of OA in MetS-OA group and nMetS-OA group respectively (p > 0.05). CONCLUSIONS: Leptin was higher and adiponectin was lower in knee osteoarthritis patients with MetS compared to those without MetS, independent of BMI. The higher SF and plasma levels of leptin in MetS-OA patients may need further studies to delineate their pathophysiological relationships.

[Bioinformatics-based identification of key genes CDC5L and related pathways in osteosarcoma and Ewing's sarcoma].

OBJECTIVE: Osteosarcoma(OS) and Ewing's sarcoma (EWS) are the two most common primary malignant bone tumors in children. The aim of the study was to identify key genes in OS and EWS and investigate their potential pathways. METHODS: Expression profiling (GSE16088 and GSE45544) were obtained from GEO DataSets. Differentially expressed genes were identified using GEO2R and key genes involved in the occurrence of both OS and EWS were selected using venn diagram. Gene ontology and pathway enrichment analyses were performed for the ensembl. Protein-protein interaction (PPI) networks were established by STRING. Further, UCSC was used to predict the transcription factors of the cell division cycke 5-like(CDC5L) gene, and GEPIA was used to analyze the correlation between the transcription factors and the CDC5L gene. RESULTS: The results showed that CDC5L gene was the key gene involved in the pathogenesis of OS and EWS. The gene is mainly involved in mitosis, and is related to RNA metabolism, processing of capped intron-containing pre-mRNA, mRNA and pre-mRNA splicing. CONCLUSION: CDC5L, as a key gene, plays a role in development of OS and EWS, which may be reliable targets for diagnosis and treatment of these primary malignant tumors.

Study on the Influencing Factors of Hypoglycemic Effect of Folate Targeted Polymersomes Encapsulating Insulin.

PURPOSE: To study the effects of the density of folic acid (FA) on the hypoglycemic ability of FA-targeted polymersomes as oral insulin carriers. Also to study the change of the hypoglycemic effect of FA-targeted mixed polymersomes added with various mass ratio of d-α-tocopherol polyethylene glycol 1000 succinate (TPGS). METHODS: The FA-targeted polymersomes with different FA molar contents were prepared. The in vitro insulin release experiments in different media for FA-targeted polymersomes with various FA contents were studied. Their quantitative cellular uptake in Caco-2 cells was examined. The in vivo hypoglycemic activity of FA-targeted polymersomes was also studied with diabetic rats. The polymersomes with the optimal FA molar content was chosen to prepare mixed polymersomes with various TPGS contents. RESULTS: Among insulin-loaded FA-targeted polymersomes with four different FA molar contents, insulin-loaded polymersomes with 10% FA molar content (insulin-loaded 10%FA-Ps) showed the hightest cellular uptake and the best hypoglycemic response. In addition, the insulin-loaded FA-Ps/TPGS5:1 mixed polymersomes exhibited higher cellular uptake and better hypoglycemic response than the other two insulin-loaded mixed polymersomes adding TPGS did. CONCLUSIONS: FA-Ps/TPGS5:1 could be a promising formulation for the oral administration of insulin.